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    MONOGRAPH FOR UKPID




    HALOPERIDOL DECANOATE




    HY Allen
    ZM Everitt
    AT Judd

    National Poisons Information Service (Leeds Centre)
    Leeds Poisons Information Centre
    Leeds General Infirmary
    Leeds
    LS1 3EX
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    MONOGRAPH FOR UKPID

    Drug name

    Haloperidol decanoate

    Chemical group

    Butyrophenone

    Origin

    Synthetic

    Name

    Brand name

    Haldol(R) Decanoate

    Synonyms

    Common names

    Product licence number

    Haldol(R) Decanoate 50mg/ml     0242/0094
    Haldol(R) Decanoate 100mg/ml    0242/0095

    CAS number

    74050-97-8

    Manufacturer

    Janssen-Cilag Limited, PO Box 79, Saunderton, High Wycombe, Bucks HP14
    4HJ
    Tel no. 01494 567567

    Form

    Intramuscular depot injection.
    NOTE: a separate entry exists for other haloperidol formulations - see
    under 'Haloperidol'.

    Formulation details

    Injection of haloperidol decanoate equivalent to 50mg/ml or 100mg/ml
    of haloperidol for intramuscular administration. Solutions contain
    sesame oil and benzyl alcohol as inactive ingredients.

    Pack size

    50 mg/ml: 5x1ml ampoules
    100mg/ml: 5x1ml ampoules

    Packaging

    Chemical structure

    C31H41ClFNO3


    Molecular weight = 530.1

    Chemical name

    4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone
    decanoate

    Indication

    Long term maintenance in schizophrenia, psychoses especially paranoid,
    and other mental and behavioural problems.

    Therapeutic dosage - adults

    By deep IM injection:
        50-300 mg every 4 weeks (reduced doses in elderly)

    Therapeutic dosage - children

        Not recommended

    Contra-indications

    Use in children, confusional states, coma caused by CNS depressants,
    parkinsonism, hypersensitivity to haloperidol, lesions of the basal
    ganglia, and during lactation.

    Abuses

    Epidemiology

    Overdose with haloperidol decanoate tends to be limited to accidental
    administration and dosage errors.

    Adverse effects

    Extrapyramidal effects such as acute dystonia, Parkinsonian rigidity,
    tremor, and akathisia. Also sedation, agitation, drowsiness, insomnia,
    headache, nausea, blurring of vision, urinary retention, hypotension,
    depression, confusional states, impairment of sexual function, skin
    reactions, epileptic fits, hyperprolactinaemia, ventricular
    arrhythmias, and abnormalities of liver function tests.

    Tardive dyskinesia, and neuroleptic malignant syndrome have both been
    associated with haloperidol therapy.

    Interactions

    PHARMACODYNAMIC

    1.  Enhancement of central nervous system depression produced by
        other CNS DEPRESSANT drugs.

    2.  Combination with other antidopaminergic agents, such as
        METOCLOPRAMIDE or PROCHLORPERAZINE increases the risk of
        extrapyramidal effects (Dollery 1991).

    PHARMACOKINETIC

    1.  The metabolism of TRICYCLIC ANTIDEPRESSANTS is impaired by
        haloperidol resulting in higher serum tricyclic levels (Stockley
        1996).

    OTHER

    1.  There is limited evidence to suggest that profound drowsiness and
        confusion may be associated with combined use of haloperidol and
        INDOMETHACIN (Stockley 1996).

    2.  Combination with high doses of LITHIUM have produced
        encephalopathic syndromes and severe extrapyramidal reactions
        (Cohen & Cohen 1974, Stockley 1996).

    ETHANOL

        Possible enhancement of central nervous system depression, and
    precipitation of extrapyramidal side effects by ALCOHOL (Stockley
    1996).

    Mechanism of action

    Haloperidol decanoate has no intrinsic activity. The pharmacological
    effects are those of haloperidol which is released by bioconversion.
    The precise mechanism of antipsychotic action is unclear, but is
    considered to be associated with the potent dopamine D2 receptor
    blocking activity of haloperidol and the resulting adaptive changes in
    the brain.
    Haloperidol is also a potent antagonist of opiate receptors, and has
    weak antagonist activity at muscarinic, histamine H1,
    alpha-adrenergic, and serotonin receptors (Dollery 1991).

    Mechanism of toxicity

    Toxicity is due to an extension of the pharmacological actions. The
    various receptor antagonist actions of haloperidol result in
    extrapyramidal reactions, orthostatic hypotension, a reduction of

    seizure threshold, hypothermia, QT and PR prolongation on the ECG,
    sedation, and antimuscarinic effects.

    Pharmacokinetics

    ABSORPTION

    Haloperidol decanoate is slowly released into the circulation where it
    is hydrolysed releasing active haloperidol. Peak plasma concentrations
    occur within 3-9 days, then decrease slowly (Beresford & Ward 1987).

    DISTRIBUTION

    Haloperidol is about 92% bound to plasma proteins (Forsman & Ohman
    1977b). It is widely distributed in the body, with an apparent volume
    of distribution of 18 L/kg (Holley et al. 1983).

    METABOLISM

    Haloperidol decanoate undergoes hydrolysis by plasma and/or tissue
    esterases to form haloperidol and decanoic acid (Beresford & Ward
    1987).

    Subsequently, haloperidol is metabolised in the liver, the main routes
    of metabolism being oxidative N-dealkylation, and reduction of the
    ketone group to form reduced haloperidol (Forsman & Larsson 1978).
    Reduced haloperidol is much less active than haloperidol but undergoes
    re-oxidation to haloperidol (Chakraborty et al. 1989, Cheng & Jusko
    1993). The cytochrome P4502D6 has been shown to be involved in the
    oxidative metabolic pathway (Llerena et al. 1992).

    ELIMINATION

    Haloperidol is excreted slowly in the urine and faeces. About 30% of a
    dose is excreted in urine and about 20% of a dose in faeces via
    biliary elimination (Beresford & Ward 1987). Only 1% of a dose is
    excreted as unchanged drug in the urine (Forsman et al. 1977). There
    is evidence of enterohepatic recycling (Chakraborty et al. 1989).

    Half-life - substance

    Haloperidol decanoate: 3 weeks

    Half-life - metabolites

    NA

    Special populations

    ELDERLY

    Haloperidol plasma concentrations in the elderly tend to be higher
    than in younger patients on equivalent doses but the difference is not
    significant (Forsman & Ohman 1977a).

    RENAL IMPAIRMENT

    It is not anticipated that renal impairment would alter the
    pharmacokinetic profile of haloperidol.

    HEPATIC IMPAIRMENT

    The clearance of haloperidol may be reduced in severe liver
    impairment.

    GENDER

    Gender has been found not to influence haloperidol plasma
    concentrations (Forsman & Ohman 1977a).

    BREAST MILK

    Haloperidol is excreted in breast milk.

    Toxicokinetics

    Absorption

    Distribution

    Metabolism

    Elimination

    Half-life - substance

    Half-life - metabolites

    Special populations

    Breast milk

    Summary

    TYPE OF PRODUCT

    Intramuscular antipsychotic depot injection.

    INGREDIENTS

    Haloperidol decanoate equivalent to 50mg/ml, or 100mg/ml of
    haloperidol.
    Formulated in benzyl alcohol and sesame oil.

    NOTE: a separate entry exists for other haloperidol formulations - see
    under 'Haloperidol'.

    SUMMARY OF TOXICITY

    Plasma concentrations of haloperidol will be greatest during the first
    week after injection. It will be during this period that there is the
    greatest risk of acute toxicity. Any symptoms occurring may take
    several weeks to resolve. Accidental injection or dose errors tend to
    be in patients on long term therapy which carries a risk of
    neuroleptic malignant syndrome and tardive dyskinesia in addition to
    acute symptoms.

    FEATURES

    Rigidity, dystonic reactions, drowsiness, and tremor.

    UNCOMMON FEATURES

    Cardiac arrhythmias, neuroleptic malignant syndrome, tardive
    dyskinesia.

    SUMMARY OF MANAGEMENT: SUPPORTIVE

    1.  Check heart rhythm and blood pressure.

    2.  Acute dystonic reactions can be managed with IV procyclidine or
        benztropine, followed by oral doses to prevent recurrence.

    3.  Other measures as required by the patients clinical condition.
        Peak plasma concentrations occur within 3-9 days of
        administration and it is during this time that symptoms are most
        likely to occur.

    Features - acute

    Ingestion

    Inhalation

    Dermal

    Ocular

    Other routes

    BY INJECTION:

    Erythema, swelling, or tender lumps at the site of injection. Acute
    dystonic reactions and other extrapyramidal signs (such as rigidity,
    and tremor), drowsiness, hypotension (or rarely hypertension),
    hypothermia, hypokalaemia, and cardiac arrhythmias particularly 

    prolongation of the QT interval and torsade de pointes (Aunsholt 1989,
    Cummingham & Challapalli 1979, Henderson et al. 1991, Scialli &
    Thornton 1978, Sinaniotis et al. 1978, Yoshida et al. 1993, Zee-Cheng
    et al. 1985).

    Features - chronic

    Ingestion

    Inhalation

    Dermal

    Ocular

    Other routes

    BY INJECTION: as for acute injection.

    At risk groups

    ELDERLY

    Increased risk of toxic events.

    PREGNANCY

    The safety of haloperidol in human pregnancy has not been established.
    There are two reports of limb defects in infants after first trimester
    use of oral haloperidol given with other potentially teratogenic drugs
    (AHFS 1998, Briggs 1994, Kopelman et al. 1975). Other investigators
    have not found an association between haloperidol and birth defects.

    CHILDREN

    ENZYME DEFICIENCIES

    The metabolism of haloperidol is subject to genetic polymorphism.
    Subjects deficient in the isoenzyme P4502D6 are poor metabolisers of
    haloperidol and will be at risk from high haloperidol plasma
    concentrations due to a reduced metabolic capacity (Llerena et al.
    1992). Approximately 7% of the caucasian population is deficient in
    this enzyme.

    ENZYME INDUCED

    Reduced risk of toxicity from haloperidol.

    Therapeutic administration with enzyme inducing drugs for a period of
    1-3 weeks results in lower haloperidol plasma concentrations (Forsman
    & Ohman 1977a, Jann et al. 1985).

    Occupations

    Others

    RENAL IMPAIRMENT: renal impairment is unlikely to increase the risk of
    toxicity.
    HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired
    metabolism.
    CARDIAC DISEASE: increased risk of cardiotoxicity due to underlying
    disease.
    EPILEPSY: increased risk of seizures due to lowered seizure threshold.

    Management

    Decontamination

    NA

    Supportive care

    MANAGEMENT OF THE SYMPTOMATIC PATIENT: SUPPORTIVE

    1. ACUTE DYSTONIC AND OTHER EXTRAPYRAMIDAL REACTIONS

    Severe dystonic reactions can be controlled within a few minutes by
    giving procyclidine or benztropine by the intravenous (or
    intramuscular) route. Subsequent oral doses may be required for 2-3
    days to prevent recurrence. Less severe extrapyramidal symptoms can be
    controlled by oral doses of procyclidine, benztropine, or other
    similar anticholinergic drug (Corre et al. 1984, Guy's, Lewisham & St.
    Thomas Paediatric Formulary 1997, BNF 1996).

    Procyclidine IV, IM:
        Adult dose:                 5-10 mg (use lower end of dose
                                    range in elderly),
        Child dose under 2 years:   500 micrograms-2 mg (unlicensed
                                    indication)
        Child dose 2-10 years:      2-5 mg (unlicensed indication).

    Procyclidine oral:
        Adult dose:                 2.5-10mg three times a day
        Child 7-14 years            1.25mg three times a day
                                    (unlicensed indication)
        Child over 14 years         2.5mg three times a day (unlicensed
                                    indication)

    Benztropine dose IV, IM, and oral:

        Adult dose:   1-2 mg (use lower end of dose range in elderly),
        Child dose:   20 micrograms/kg (unlicensed indication).

    2. HYPOTENSION

    Hypotension should be managed by the administration of intravenous
    fluids and by physical means. Where these measures fail, consideration
    may be given to the use of a direct acting sympathomimetic such as
    noradrenaline with appropriate haemodynamic monitoring (e.g. insertion
    of Swan-Ganz catheter).

        ADULT DOSE: IV infusion of noradrenaline acid tartrate 80
    micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) in
    dextrose 5% via a central venous catheter at an initial rate of 0.16
    to 0.33 ml/minute adjusted according to response (BNF 1998).
        CHILD DOSE (unlicensed indication): IV infusion of noradrenaline
    acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1
    microgram/kg/minute of noradrenaline base) in glucose 5% or
    glucose/saline via a central venous catheter (Guy's, Lewisham & St
    Thomas Paediatric Formulary 1997).

    NOTE: sympathomimetics with mixed alpha and beta adrenergic effects
    (e.g. adrenaline or dopamine) should not be used as they may aggravate
    hypotension.

    3. CARDIAC ARRHYTHMIAS

    The ventricular arrhythmia, torsade de pointes, may prove difficult to
    manage. Treatment is aimed at shortening the QT interval by
    accelerating the heart rate. The preferred method is by CARDIAC
    OVERDRIVE PACING (Henderson et al. 1991).

    Alternatively isoprenaline may be used to increase the heart rate, but
    with caution, as the unopposed beta 2-adrenergic agonist effects will
    exacerbate hypotension.
        ADULT DOSE: intravenous isoprenaline infused at a starting dose
    of 0.2 micrograms/minute and titrated to maintain a heart rate of 100
    beats per minute (Kemper et al. 1983).

    Intravenous magnesium sulphate has also been shown to be effective in
    the management of torsade de pointes (Tzivoni et al. 1988).

        ADULT DOSE; 8 mmol of magnesium sulphate (4 ml of 50% solution)
    by intravenous injection over 10-15 minutes, repeated once if
    necessary (BNF 1998). CHILD DOSE: clinical experience in children is
    lacking, but based on the above recommendations for management in
    adults, doses of 0.08-0.2 mmol/kg (0.04-0.1 ml/kg of 50% solution) may
    be considered appropriate (based on Guy's, Lewisham & St Thomas
    Paediatric Formulary 1997).

    4. TEMPERATURE DISTURBANCES

    Where the patient is hypothermic the body temperature should be
    allowed to recover naturally by wrapping the patient in blankets to
    conserve body heat.

    Conventional external cooling procedures should be used in patients
    who are hyperthermic.

    5. NEUROLEPTIC MALIGNANT SYNDROME

    The development of NMS with a high central temperature (over 39C) is
    best treated by paralysing and mechanically ventilating the patient.
    This usually controls the muscle spasm and allows the temperature to
    fall. If the body temperature is 40C or over, administer intravenous
    dantrolene.

        ADULT DOSE: dantrolene 1 mg/kg body weight by rapid IV injection
    repeated as required to a cumulative maximum of 10 mg/kg (BNF 1998).

    Monitoring

    Check the heart rate and rhythm, blood pressure, and body temperature
    during the first 7-10 days after administration. Correct any
    electrolyte abnormalities.

    Antidotes

    None available.

    Elimination techniques

    None.

    Investigations

    Management controversies

    Case data

    Analysis

    Agent/toxin/metabolite

    The measurement of plasma haloperidol is of little benefit as no
    correlation has been established between plasma haloperidol
    concentration and therapeutic or toxic effect.

    Sample container

    NA

    Storage conditions

    NA

    Transport

    NA

    Interpretation of data

    It has been suggested that a plasma haloperidol concentration of
    0.005-0.012 mg/L may be associated with a clinical response, but this
    range should only be viewed as a rough guide (Van Putten et al. 1992).
    Peak concentrations following depot injection have been in the range
    0.001-0.050 mg/L with steady-state concentrations around 0.008 mg/L
    (Nayak et al. 1987).

    Conversion factors

    Others

    NA

    Toxicological data

    Carcinogenicity

    An increase in mammary neoplasms has been observed in rodents
    following long term administration of prolactin-stimulating
    antipsychotic agents. Although no association between human breast
    cancer and long term administration of these drugs has been shown,
    current evidence is too limited to be conclusive (AHFS 1998).

    Genotoxicity

    Mutagenicity

    Reprotoxicity

    Hyperprolactinaemia resulting from haloperidol therapy may lead to
    infertility in women and impotence in men.

    Teratogenicity

    Haloperidol has been shown to be teratogenic and fetotoxic in animals
    at dosages 2-20 times the usual maximum human dosage (AHFS 1998).
    In human pregnancy, haloperidol has not been associated with
    teratogenic effects when used alone, but there are two reports of limb
    defects following the first trimester administration of haloperidol
    with other drugs (Briggs 1994, Kopelman et al. 1975).

    Relevant animal data

    Relevant in vitro data

    Authors

    HY Allen
    ZM Everitt
    AT Judd

    National Poisons Information Service (Leeds Centre)
    Leeds Poisons Information Centre
    Leeds General Infirmary
    Leeds
    LS1 3EX
    UK

    This monograph was produced by the staff of the Leeds Centre of the
    National Poisons Information Service in the United Kingdom. The work
    was commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Prepared October 1996
    Updated May 1998

    References

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    Beresford R, Ward A.
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    BNF.
    Joint Formulary Committee. British National Formulary, Number 35.
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    Briggs GG, Freeman RK, Yaffe SJ.
    Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams &
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    Chakraborty BS, Hubbard JW, Hawes EM, McKay G, Cooper JK, Gurnsey T,
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    Cheng H, Jusko WJ.
    Pharmacokinetics of reversible metabolic systems. Biopharm Drug Dispos
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    Cohen WJ, Cohen NH.
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    Cummingham DG, Challapalli M.
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    Forsman A, Ohman R.
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    Kemper AJ , Dunlap R, Pietro DA.
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    Kopelman AE, McCullar FW, Heggeness L.
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    Yoshida I, Sakaguchi Y, Matsuishi T, Yano E, Yamashito Y, Hayata S,
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    See Also:
       Toxicological Abbreviations